Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, PR China.
Eur J Pharmacol. 2013 Apr 5;705(1-3):26-34. doi: 10.1016/j.ejphar.2013.02.005. Epub 2013 Mar 7.
TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising anticancer agent as it specifically kills a wide variety of cancer cells. However, resistance of subpopulations of cancer cells to TRAIL-induced cell death remains a major obstacle for successful treatment of cancer using TRAIL-based therapy. In this report we show that the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) efficiently enhances TRAIL-induced apoptosis through downregulation of receptor-interacting protein kinase 1 (RIP1) in breast cancer cells. Although 2-DG alone did not kill breast cancer cells, it sensitized the cells to TRAIL-induced cell death. This could be efficiently inhibited by blockage of the caspase cascade, suggesting 2-DG augments TRAIL-mediated apoptotic signaling. Indeed, treatment with 2-DG resulted in upregulation of TRAIL receptor 2 (TRAIL-R2), downregulation of cIAP1 and XIAP, and reduction in RIP1. The latter appeared to play an important role in regulating sensitivity of breast cancer cells to TRAIL, in that knockdown of RIP1 recapitulated, at least in part, the effect of 2-DG on TRAIL-induced apoptosis. Taken together, these results indicate that 2-DG enhances TRAIL-induced apoptosis in breast cancer cells by multiple mechanisms including suppression of RIP1, and highlight the potential therapeutic benefit of combinations of 2-DG and TRAIL in the treatment of breast cancer.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）似乎是一种很有前途的抗癌药物，因为它能特异性地杀死多种癌细胞。然而，癌细胞亚群对 TRAIL 诱导的细胞死亡的抵抗仍然是使用 TRAIL 为基础的治疗成功治疗癌症的主要障碍。在本报告中，我们表明己糖激酶抑制剂 2-脱氧-D-葡萄糖（2-DG）通过下调乳腺癌细胞中的受体相互作用蛋白激酶 1（RIP1），有效地增强 TRAIL 诱导的细胞凋亡。虽然 2-DG 本身不能杀死乳腺癌细胞，但它能使细胞对 TRAIL 诱导的细胞死亡敏感。这可以通过阻断半胱天冬酶级联反应有效地抑制，表明 2-DG 增强 TRAIL 介导的凋亡信号。事实上，用 2-DG 处理会导致 TRAIL 受体 2（TRAIL-R2）的上调，cIAP1 和 XIAP 的下调，以及 RIP1 的减少。后者似乎在调节乳腺癌细胞对 TRAIL 的敏感性方面起着重要作用，因为敲低 RIP1 至少部分地再现了 2-DG 对 TRAIL 诱导的细胞凋亡的作用。总之，这些结果表明，2-DG 通过多种机制增强乳腺癌细胞中 TRAIL 诱导的细胞凋亡，包括抑制 RIP1，并强调了 2-DG 和 TRAIL 联合治疗乳腺癌的潜在治疗益处。
